The therapeutic effectiveness of many drugs is reduced by their lack of solubility in water and permeability into tissues. In recent years polymeric particles have emerged as attractive drug administration systems. Particles are used to encapsulate a variety of drugs for controlled delivery and improved solubilization. Because of their smaller size they generally exhibit greater intra-cellular uptake and are suitable for administration of drugs through various routes, such as orally, parenterally and oculary. (Kreuter, Adv. Drug Del. Rev., 7.71-86 (1991); Gref et al., Science, 263:1600-1603 (1994); Zimmer and Kreuter, Adv. Drug Del. Rev., 16:61-73 (1995)). The controlled release of drugs allows prolonging the effect of molecules with low biological half-lives, prevents over-dosage and lowers toxic side effects. Moreover, by incorporating molecules with different physico-chemical features, these carriers can be modified to achieve variable release rates or to target specific organs or cells.
Despite their potential advantages, conventional particles have significant drawbacks with respect to their use in drug administration. Their instability in gastrointestinal fluids, a low degree of intestinal absorption, and non-specific adhesion, reduce their utility in oral administration. Parenteral administration can overcome some of these problems by specifically targeting drugs to certain organs. However, particles are quickly recognized, taken up and eliminated from the blood circulation by macrophages of the mononuclear phagocyte system (MPS) after their intravenous administration. This phenomenon limits their function in controlled release and reduces their effective concentration in the tissues.
Modification of the characteristics of the polymeric matrix and the surface of the particles may provide solution to some of the problems described above. One possible modification is pegylation or attaching polyethylene glycol (PEG) to particles. The association of polyethylene glycols to particles protects them from enzymatic attacks in digestive fluids. PEG coated particles have demonstrated prolonged circulation and longer plasma half-life. (Gref et al., Science, 263:1600-1603 (1094); Stolnik et al., Pharm. Res., 11:1800-1808 (1994); Verrecchia et al., J. Controlled Rel., 36:49-61(1995)). The flexible and hydrophilic PEG chains apparently provide a steric stabilization that reduces protein interaction and uptake by macrophages. (T. M. Allen et al., Biochimica et Biophysica Acta, 1068: 133-141 (1991); Mosquiera et al., Biomaterials, 22:2967-2979 (2001))
However, physical instability (aggregation) and/or chemical instability (hydrolysis) have been observed when these particles are stored for extended period. Also, aqueous formulations containing protein are susceptible to microbial contamination because proteins are good substrates for microbial growth. In order to circumvent these problems, water has to be removed from these systems. Thus, injectable particles are preferably stored as dry powder in order to ensure ease of handling and transportation. A commonly used process that converts solutions or suspensions into solids is freeze-drying or lyophilization. It involves removing water from a frozen sample by sublimation and desorption under vacuum. A significant challenge encountered during the formation of such solid dried forms of particles is the difficulty in reconstituting the particles to their original size. Another commonly used process that converts solutions or suspensions into solids is freezing. Frozen suspensions also present a similar challenge in recovering particles to their original size upon thawing. The presence of PEG chains causes the individual particles to aggregate via entanglement and subsequent crystallization of the PEG chains during the freeze-dry cycle. However, for an intravenous administration of particles a mean particle size of 100-200 nm and a homogenous size distribution is needed to avoid the risk of embolism and to enable sterile filtration.
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.